The mortality in heart failure is high, with ˜50% of patients dying within 5 years of diagnosis. One of the most promising treatments for heart failure is administration of β-adrenergic receptor antagonists (often called “β-blockers”).
There are at least nine sub-types of adrenergic receptors (H. G. Dohlman et al., Annu. Rev. Biochem. 60:653-688 (1991); S. B. Liggett et al., In: Catecholamines, Bouloux, ed. W. B. Sounders, London (1993)), of which at least three sub-types are β-adrenergic receptors, namely β1-, β2-, and β3-adrenergic receptors. These beta adrenergic receptors (β-AR) bind to endogenous catecholamines, epinephrine (adrenaline) and norepinephrine (noradrenaline).
The β1- and β2-adrenergic receptors (β1-AR and β2-AR) are expressed in many organs in the body, including heart, lung, vascular tissue, and pancreas (S. B. Ligget In: The Lung: Scientific Foundations, R. G. Crystal et al. (ed.) Lippincott-Raven Publishers, Philadelphia (1996); J. R. Carstairs et al., Am. Rev. Respir. Dis. 132:541-547 (1985); Q. A. Hamid et al., Eur. J. Pharmacol. 206:133-138 (1991)). In the heart, one or both of these receptors regulate heart rate and pumping function. In addition, these receptors mediate the actions of adrenaline and noradrenaline, as well as a host of synthetic agonists as well.
Both β1-AR and β2-AR have been cloned and sequenced (T. Frielle et al., Proc. Natl. Acad. Sci. (USA) 84:7920-7924 (1987) and B. K. Kobilka et al., Proc. Natl. Acad. Sci. (USA) 84:46-50 (1987)). The β1-AR gene has been localized to chromosome q24-q26 of chromosome 10 (T. L. Yang-Feng et al., Proc. Natl. Acad. Sci. (USA) 87:1516-1520 (1990)), while the intronless gene of β2-AR has been localized to q31-q32 of chromosome 5. The human β1-AR and β2-AR are 477 amino acids and 413 amino acids long, respectively, and they are structurally similar in many respects.
The human heart expresses both β1-AR and β2-AR subtypes (M. R. Bristow et al., Mol. Pharmacol. 35:296-303 (1988)). Each receptor mediates positive inotropic and chronotropic responses to endogenous catecholamines and exogenously administered agonists (E. O. Brodde et al., J. Cardiovasc. Pharmacol. 8:1235-1242 (1986); 0. E. Brodde et al., Z. Kardiol. 81:71-78 (1992)).
Thus, the administration of β-blockers provides the therapeutic benefit in heart failure. However, there is a very high degree of variability in the treatment response to these agents (M. M Givertz, N. Engl. J. Med. 342:1120-1122 (2000)). Further, tests to predict which patients will respond are not currently available, leading to a “trial-and-error” method to tailor the treatment to the patient, and thus ultimately suboptimal care is provided. Thus, there is a need in the art for improved methods to identify these polymorphisms and to correlate the identity of these polymorphisms with functions of β-adrenergic receptors. The present invention addresses these needs and more by providing polymorphisms, molecules, and methods useful for the diagnosis or risk assessment, predicting relative efficacy of β blocker therapy, and prognosis of cardiovascular diseases, obesity, and diabetes.